Clinics in Dermatology (2014) 32, 488–501

Autoinflammatory syndromes forthe dermatologist

Paula Dávila-Seijo, MD, Angela Hernández-Martín, MD, Antonio Torrelo, MD⁎

Department of Dermatology, Hospital del Niño Jesús, Menéndez Pelayo 65, 28009 Madrid, Spain

Abstract While autoimmunity as cause of disease is well-established, other categories of immune-mediated diseases that are not produced by targeting of self-antigens by antibodies is in the process ofbeing described. These so-called autoinflammatory diseases arise when an inappropriate activation ofantigen-independent mechanisms occurs.

Autoinflammatory diseases course with recurrent attacks of fever and multisystemic inflammation;however, the skin may also be affected by a variety of inflammatory manifestations that often alert theclinician about the presence of an autoinflammatory disease. Recognizing the cutaneous features ofthese syndromes will aid for prompt diagnosis and early treatment that is key for the quality of life andsurvival of the affected patients.

In this paper, we focus on the skin manifestations of autoinflammatory diseases in children, which isthe usual period of appearing of the first symptoms and signs.© 2014 Elsevier Inc. All rights reserved.

Introduction

The primitive arm of the immune response, the innateimmune system, constitutes the first line of defense againstpathogens and harmful stimuli. The innate immune system isantigen-independent; activity is based on recognition ofmolecular markers of infection or injury by the so-called“pattern recognition receptors,” which activate multipleinflammatory signaling cascades and the main cellulareffectors of innate immunity: macrophages, neutrophils,mast cells, and natural killer cells. When inappropriateactivation of the innate immune system appears it mayproduce an autoinflammatory disease, in contrast to the well-known phenomenon of autoimmune diseases caused byaberrations in the adaptative immune system.1–3

The best described autoinflammatory diseases (see Table 1)are the “autoinflammatory syndromes,” a group of rareconditions produced by mutations in single genes that codifyproteins playing a crucial role in different inflammation

⁎ Corresponding author. Tel.: + 34 91 5035900; fax: + 34 91 5744669.E-mail address: atorrelo@aedv.es (A. Torrelo).

http://dx.doi.org/10.1016/j.clindermatol.2014.02.0040738-081X/© 2014 Elsevier Inc. All rights reserved.

pathways of the innate immune system.1 These syndromeshave in common the presence of: (1) recurrent systemicinflammation signs and symptoms that appear early in life,usually during childhood; (2) genetic transmission in mostcases; and (3) the presence of different skin manifestations thatconstitute a characteristic part of the clinical spectrum.Pediatricians, dermatologists, and pediatric dermatologistsplay an important role in the recognition of these rare butcharacteristic diseases.

In this paper, we have tried to give an overall updatedvision of all autoinflammatory syndromes with dermatologicfeatures that have been previously reported in the literature,focusing on etiopathogenesis, genetics advances, and clinicalmanifestations, with a particular emphasis on the features.

Hereditary periodic fever syndromes (HPFS)

HPFS include a few autoinflammatory disorders charac-terized by recurrent episodes of fever, appearing at variableintervals from days to weeks, in conjunction with several

489Autoinflammatory syndromes

clinical manifestations of systemic inflammation caused bymutations in single genes that encode proteins with majorroles in the innate immune system.

Table 1 Autoinflammatory diseases with dermatologicmanifestations

• Periodic fever syndromes (PFS):o Familial Mediterranean fever (FMF)o Tumor necrosis factor receptor-associated periodic syn-drome (TRAPS)

o Hyperimmunoglobulinemia D syndrome (HIDS)o Periodic fever with aphtous stomatitis, pharyngitis, andadenitis syndrome (PFAPA)

• Cryopirin-associated periodic syndromes (CAPS):o Familial cold autoinflammatory syndrome (FCAS)o Muckle-Wells syndrome (MWS)o Neonatal onset multisystemic inflammatory disorder(NOMID)

• Generalized pustular syndromes:o Deficiency of the interleukin-1-receptor antagonist syn-drome (DIRA)

o Deficiency of interleukin thirty-six-receptor antagonistsyndrome (DITRA)

• Other autoinflammatory syndromes:o Pyogenic arthritis, pyoderma gangrenosum and acne syn-drome (PAPA)

o NOD2-associated pediatric granulomatous arthritis (PGA):Blau syndrome/early-onset sarcoidosis.

o Majeed syndromeo Chronic atypical neutrophilic dermatosis with lipodystrophyand elevated temperature (CANDLE) syndrome and otherproteasome related diseases

• Beçet syndrome• Schnizltler syndrome• SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis)

syndrome• Chronic recurrent multifocal osteomyelitis (CRMO) spo-

radic form• Systemic juvenile idiopathic arthritis (Still disease) and adult

onset• Pyoderma gangrenosum, acne, and suppurative hidradenitis

(PASH)• Possible autoinflammatory diseases:o Inflammatory bowel diseaseo Sweet syndrome, pyoderma gangrenosum, and other neu-trophilic dermatoses

Familial Mediterranean fever (FMF)

FMF, the paradigm of the periodic fever syndromes, is anautosomal recessive (AR) disorder, common among Arme-nians, Italians, North Africans, Sephardic Jews, and Turks,having been less commonly reported in a variety of otherethnicities.4 There is an extraordinary high number of FMFcarriers in Middle Eastern populations, suggesting some kindof advantage to individuals who are heterozygotes.5

The FMF gene, called MEFV (standing for MEditerra-nean FeVer), is located at chromosome 16 p and encodes aprotein named pyrin (marenostrin) expressed in the cyto-plasm of myeloid-derived circulating cells, synovial fibro-blasts, and dendritic cells.6,7 Pyrin plays a major role in theinnate immune system as a main regulatory component of theNLRP3 inflammasome, a large protein complex composedof pyrin, ASC (apoptosis-associated specklike protein with aCARD), caspase 1, and cryopyrin. The inflammasomes takepart in multiple inflammation signaling pathways such as theNFκB and IL-1 β pathways.8

Eighty percent of MEFV mutations are missensemutations, located at one of three sites encoded on exon10.9 Others mutations are located at exon 2 of chromosome16.5 The 694 and 726 position mutation sites are the mostwidely distributed. M694V mutation is by far the mostfrequent in FMF and is associated with early onset, arthritis,erysipeloid-like skin lesions, oral lesions, splenomegaly,renal amyloidosis, higher fever, and more frequent attacks.Patients with these mutations usually require higher doses oftreatment to prevent attacks.10–12 The second most frequentmutation is V726A. There are a proportion of patients (up to25%) who have a single MEVF mutation and who presentclinical manifestations identical to homozygous patients, butusually in a milder form.13,14

Incomplete penetrance and variable clinical expression isseen among FMF patients, even in those who have the samemutation. This suggests the role of some mitigatingenvironmental or genetic factors, which could modify theexpression of systemic manifestations of FMF.15 One suchfactor is the presence of major histocompatability class I(MHC Class I) chain-related gene A alleles, which areassociated with different clinical manifestations in FMFpatients. For example, the A9 allele is related to early onsetand A4 with lower frequency of attacks.16

It seems that neutrophils are the effector cells in serosalinflammation. They appear in high number in serosal fluidsduring attacks and express pyrin in their cytoplasm;colchicine, a neutrophil suppressor, has proven effective inpreventing the attacks.9 Deficit of the C5a/IL8 inhibitorsmay also play a role in FMF pathogenesis. This serinprotease, which blocks C5a and IL-8, two potent neutrophil

chemotactic factors, has been found in low levels in serousfluids among FMF patients.17,18

The hallmark of FMF are episodic attacks of fever, thattypically last less that 72 hours, together with abdominal pain(95%), pleurisy (30%), mono or oligoarticular arthritis(75%), and/ or arthralgias.19 The arthritis may appearindependently of the other clinical manifestations and itmay last even months. Pericarditis or acute scrotal pain andswelling may be present but only rarely.5,20 Attacks are self-limited and between them the patient remains asymptomatic.The lapse between attacks is very variable. Possible attackstriggers are vigorous exercise, emotional stress, exposure toextreme temperatures, and hormonal changes.19 FMF begins

490 P. Dávila-Seijo et al.

typically in childhood. In 65% of patients the first attackoccurs before 10 years of age and 90% appears before 20.21

AA amyloidosis, caused by a deposit of serum amyloid Aprotein, is a severe complication that could appear inuntreated patients and could produce renal and hepaticdysfunction. Amyloidosis is not always correlated with thefrequency or intensity of attacks and evidenced inflamma-tion. This observation suggests that there would be otherfactors, including some mutations, that increase or decreasethe risk of developing amyloidosis.15 During acute attacksthere appears an elevation of many of the serum markers ofsystemic inflammation, such as erythrocyte sedimentationrate (ESR), beta-2 microglobulin, C-reactive protein (CRP),serum amyloid protein (SAA), fibrinogen and leukocytosiswith a predominance of neutrophils is common.19

Erysipeloid-like lesions, which appear in 15% to 20% ofchildren, are the distinctive cutaneous manifestation ofFMF.22–24 They are usually present in the lower extremities,on the anterior surface of the leg, below the knee, and thedorsum of foot. They appear as well-circumscribed edem-atous and erythematous plaques, bilateral or isolated, nolarger than 15 cm in diameter. Pathologic studies of theselesions have revealed a predominantly neutrophilic infiltratewith nuclear dust.25 Purpuric lesions on the face, trunk, andextremities have also been reported in children. Henoch-Schönlein purpura (5% of children) and polyarteritis nodosaare present with higher frequency in FMF patients.26–29

Colchicine, a neutrophil suppressor of choice is theelective drug in FMF patients. There is good evidence thatthe use of colchicine continuously reduces the frequency, theintensity and the duration of the attacks and also decreasesthe risk of developing amyloidosis. Colchicine could alsoabort an attack if it is taken during the prodomal phase.Colchicine is safe in long-term therapy in children. Theinitial and the maintenance dose vary with age and the needsto control symptoms, but usually they are between 0.5 to 1.8mg/day. Colchicine should be introduced after a diagnosis ofFMF is made and it should be maintained for life.30

In patients who do not respond to colchicine, it isimportant to verify the compliance with therapy. Intravenouscolchicine could be tried as some of these not-responders dorespond to this regime. There are isolated reported cases oftruly colchicine-resistant patients that responded to thalido-mide, to anti-TNFα agents such as etanercept and infliximab,and to the recombinant IL-1 receptor antagonistanakinra.31,32

Tumor necrosis factor receptor-associated periodicsyndrome (TRAPS)

TRAPS, also known as familial Hibernian fever (becauseit was firstly described in an Irish family), is a rare autosomaldominant (AD) disease that causes fever and localinflammation that typically last between 7 to 21 days.33,34

TRAPS is caused by a genetic mutation in the gene TNFRsuperfamily IA, localized in the short arm of chromosome 12

p13.35,36 Its product, the tumor necrosis factor receptor(TNFR), is a 55 kDa protein that serves as an antagonist tocirculating TNF and plays a role in cellular functions relatedto pyrexia, cachexia, cytokine production, leukocyte activa-tion, expression of adhesion molecules, and resistance tocellular pathogens. To date more than 50 mutations havebeen reported.5

Clinically, TRAPS patients have recurrent episodes, usuallylasting longer than 5 days but less than 1 month, of fever,myalgia with a characteristic distal migration (seen in 80% ofpatients), arthralgias, severe abdominal pain usually associatedwith gastrointestinal symptoms and conjunctivitis.5,33 Thereare also reported cases without fever.37 Systemic AAamyloidosis develops in 8% to 25% of the affected leadingto impaired renal and/or hepatic function. It seems that patientswith mutations involving the aminoacid cysteine and the T50M mutation of TNFRSF1 A have an increased risk ofdeveloping AA amyloidosis.38 The age of TRAPS onset isvariable and ranges from 2 weeks to 53 years.39

Laboratory analyses show an elevation of inflammatorymarkers such as erythrocyte sedimentation rate (ESR) andC-reactive protein (CRP), especially during attacks.Antinuclear antibodies (ANA) and rheumatoid factor arerarely present.33

Patients who present with cutaneous lesions are 69% to87%. The most frequent skin lesion (seen in 40%) is acentrifugal migratory, erythematous patch overlying the areawith myalgia, also called “painful erythema.” Typically,these lesions move from proximal to distal site over a periodof minutes to several days. Frequently, the eythematouspatch is associated with an underlying myalgia that alsomigrates concomitantly. Other lesions consist in urticarial-like plaques and generalized erythematous macular andpapular lesions that, over time, coalesce in larger annular orserpiginous patches and plaques. Thirty-six percent of skinlesions resolve with an ecchymotic appearance.

Pathological examination reveals perivascular and inter-stitial infiltrate of mononuclear cells. Immunofluorescencestudies of cutaneous lesions show IgM and C3 deposits atdermal-epidermal junction or diffuse IgA, IgG, and C3deposition. Small vessel vasculitis and recurrent panniculitishave rarely been associated with TRAPS.34

TRAPS responds to treatment with oral corticosteroids.Unfortunately, colchicine has no therapeutic effect. Etaner-cept, a soluble p75 TNFR-Fc fusion protein, can decreasebut not eliminate the symptoms. The hypothesis that adefective shedding of surface TNFR in TRAPS causes acontinuous activation signal would explain the results ofanti-TNF drugs in treating TRAPS. Treatment with otheranti-TNF drugs, such as infliximab, can precipitate para-doxical attacks. Better results are obtained with anakinra,raising a new hypothesis in which intracellular aggregationof misfolded TNFR1 causes hyperimmune responses that isindependent of TNF and mediated by enhanced productionof mitochondrial-derived oxygen reactive species thatdisturb intracellular homeostasis.40

491Autoinflammatory syndromes

Hyperimmunoglobulinemia D syndrome (HIDS)

HIDS is an AR disease characterized by recurrentepisodes of fever associated with lymphadenopathy, gastro-intestinal symptoms, and elevated levels of Ig D. About 50%of patients with HIDS are of Dutch ancestry.41,42

HIDS can be divided into two forms: classic and variantform. Classic HIDS includes cases in which the geneticmutation is known (about 75% of all HIDS cases). In variantHIDS, the clinical picture is the same as in classic HIDS, butthe genetic bases are still unknown.43

The gene for classic HIDS is the mevalonate kinase(MVK) gene located in chromosome 12 q24.44 Most patientsare heterozygous for two different mutations in MVK gene:one of these mutations, when present in a homozygous state,causes mevalonic aciduria but the mutation in the other allelein HIDS is not typical for mevalonic aciduria. The mostfrequent mutation in homozygous HIDS patients is theV377I that appears in 50% of cases.45 MVK is an enzymethat plays a role in the synthesis of the cholesterol/isoprenoids pathway. In HIDS there is a remaining activityof MVK, something that differentiates HIDS from mevalonicaciduria where the MVK function is completely absent. Thegene defects associated with HIDS produce a temperature-dependant MVK, the activity of which is impaired byincreasing temperature at a greater rate than normal MVKenzyme. In mevalonic aciduria the MVK activity is nottemperature dependant.46,47

Although IgD levels are typically, but not always, elevatedin HIDS they do not seem to be responsible of the clinicalmanifestations of HIDS because the levels do not correlatewith the severity for frequency of the attacks. There is noclarity regarding what role IgD plays in HIDS pathophysi-ology, but the latest theories indicate that this elevation is asecondary phenomenon due to systemic inflammation.48

It is hypothesized that HIDS attacks start with a trigger(such as trauma, vaccinations, or stress) capable of inducingelevation in body temperature. Due to the heat-sensitivity of

Fig. 1 NOMID syndrome. Hyperteolorism, frontal bossing, andurticarial lesions.

MVK in HIDS, a decreased activity in the enzyme activitywould lead to downstream of nonsteroid isoprenoidsproducing a proinflammatory state with further aggravationof fever and inflammatory symptoms. Eventually, thehomeostasis is restored and the attack ends.49

Clinical manifestations in HIDS begin during the firstyear of life. They are characterized by episodic attacks offever (usually more than 38.5 °C) that last from 4 to 7 days.Some patients describe prodromal symptoms such asheadache, fatigue, and nasal congestion. During the attacksother clinical symptoms noted include (1) localized orgeneralized tender lymphadenopathy (90% of patients), (2)abdominal pain that can mimic acute abdomen (almost100% of patients), (3) palpable splenomegaly (50%), and/or(4) polyarticular joint involvement (80%), with arthralgiaand/or arthritis that is usually symmetric with a predilectionfor the large joints. Joint affectation may last longer thanfebrile attacks, but there has never been reported any long-term join destruction.48

Seroritis, orbital tendonitis with tendomyositis, mayoccur, but rarely.50 One case of nummular keratopathy wasreported, as well.51 Amyloidosis is an infrequent seriouscomplication of HIDS.52

The periodicity of attacks is variable (4 to 8 weeks), but inchildren and adolescents the periods between attacks areshorter than adults. HIDS patients remain asymptomatic inthese interval periods with the exception of joint and skinmanifestations that may last longer.5,49

In the HIDS variant, the clinical manifestation of HIDSmay appear later in life, even in adulthood. The periodicity ofattacks is more variable than in classic HIDS.49

Laboratory analyses frequently show a polyclonal IgDelevation (N14 mg/dL), but normal levels are also possi-ble.48,53 IgA elevation (greater than 260 mg/dL) is also seenin 80% of the affected. Other inflammatory markers areelevated as well.48

Cutaneous manifestationsHeterogeneous skin lesions appear up to the 80% of the

patients with HIDS. They usually consist in macularerythematous eruption composed of solitary lesions thatmay coalesce. They favor the acral parts over the trunk.Other skin lesions that may be present in HIDS are papules,erythematous nodules, urticarial lesions, and petechiae.Microscopic examination usually shows endothelial swellingand perivascular inflammatory infiltrates. Henoch-Schönleinpurpura, erythema elevatum diutinumlike, sweetlike, cellu-litislike lesions and deep vasculitis have also been reportedin HIDS.5,48,54

TherapyThe mainstream HIDS management is symptomatic

therapy during attacks. The most used drugs are nonsteroidalantiinflammatory drugs (NSAIDs). There is no predilectionagent. NSAIDs can be started during the prodomal phase andmaintained until the episode ends. In patients who do not

ig. 2 Arthropathy in NOMID syndrome: Knee swellings andrticarial lesions.

492 P. Dávila-Seijo et al.

respond to NSAIDs a short course of oral corticosteroidsmay be used. Doses vary from a single pulse dose at thebeginning of symptoms to 1 mg/kg of prednisone orprednisolone daily for 4 to 7 days or even 2 weeks toalleviate the joint symptoms.

Other agents such as colchicine, cyclosporin, intravenousimmunoglobulin G, statins, and thalidomide showed nobeneficial effects in HIDS. Etanercept was used in severalcases with variable results, but it seems to have some benefitin the rare cases with syndrome-overlap with TRAPS. So far,there are only a few reported cases of HIDS patients treatedsuccessfully with anakinra.55

Periodic fever with aphtous stomatitis, pharyngitis,and adenitis syndrome (PFAPA)

PFAPA is the most common of all periodic feversyndromes, and unlike the others it is a sporadic conditionin which familial cases are sparse.56 Characteristically itbegins during childhood, commonly between 2 and 5 yearsof age and resolved before the end of first decade. There is amild male predominance and PFAPA does not show higherincidence in any ethnicity.57,58

EtiologyTo date there are no identified mutations in PFAPA and

the etiology remains unknown. There is an alteredinflammatory cytokine profile during attacks in PFAPAand the cellular immune response is different from what isseen in infections. In addition, there is an activation of theinnate immunity and an elevation of IL-1 beta secretion thatmight precipitate the attack.58,59 The similarities betweenPFAPA and cyclic neutropenia prompt the idea of commonpathways of immune dysfunction. They are truly periodicfever syndromes with a cyclic occurrence of episodes, but inPFAPA syndrome neutropenia is not found.60

The carrier state of MEVF, the familial Mediterraneanfever gene, seems to act as a gene modifier of PFAPAassociated with shorter duration of attacks, longer duration ofattacks-free periods, and less oral lesions.61

Clinical manifestationsPatients present abrupt episodes of fever that last 3 to 6

days and recur every 3 to 4 weeks, and may associate one ormore of the following symptoms: aphtous stomatitis,exudative or nonexudative pharyngitis, tender cervicallymphadenopathy, and mild abdominal pain. Other lessspecific symptoms are fatigue, myalgias and headache.57

Laboratory analyses during the attacks show moderateleukocytosis and elevation of ESR and CRP that return tonormal once the attack ends.

Cutaneous manifestationsAphtous ulcers occur in 40% to 70% of PFAPA patients.

They are usually small, appear in low number on the lips or

Fu

oral mucosa and heal without scarring. A nonspecific skinrash was rarely reported during attacks.60

TherapyPFAPA is a self healing condition, which usually

disappears with age. Growth and development are preservedand no long-term sequelae are seen. Treatment is an option inwhich benefits need to be pondered against risks.

Antipyretics and NSAIDs are only effective for fever.Systemic corticosteroids, such as prednisone in doses of 1 or2 mg/kg/day, lead to a dramatic relief of fever andpharyngitis in a couple of hours, but neither the aphthaenor the lymphadenopathy tend to improve. Up to 25% ofaffected children who are treated with corticosteroids presentan increased frequency of febrile attacks, even weekly, as aside effect. This may limit the use of steroids as therapy insuch cases. The most common dosage is one single dose of 2mg/kg of prednisone at the beginning of fever; if there is norecurrence at 48 to 72 hours, the dose could be decreased to 1mg/kg for 2 days and then to .5 mg/kg for another 2 days.Lower single doses of prednisone (.5 to 1.5 mg/kg/day) alsoshowed good results in aborting the attack in severaluncontrolled series.

Cimetidine use (20 to 40 mg/kg/day in divided doses)has been reported to be beneficial in reducing oreliminating the recurrence of episodes in small case series.In three cases, the response was maintained once drug wasdiscontinued after 6 months.

Prophylaxis with colchicine (.5 to 1 mg/day) may inducea longer episode-free interval, but results are inconsistent andit is not routinely recommended.

Tonsillectomy shows beneficial effect in most but not allPFAPA patients, but recurrence appears in up to one third oftreated patients. Taking into account that PFAPA is a benigncondition tonsillectomy does not seem an adequate first-therapy option.60

493Autoinflammatory syndromes

Cryopyrin-associated periodic syndromes (CAPS)

The CAPS, also called cryopyrinopathies, are a group ofthree rare, overlapping autoinflammatory syndromes thatshare a common etiology: all are due to different mutations inthe NLRP3 gene (also called CIAS1) localized at chromo-some 1 q44. All of them are autosomal dominant diseaseswith variable penetrance. NLRP3 product is the proteincalled cryopyrin (NALP3 or PYPAF1). Cryopyrin is part of amultiprotein inflammasome complex (the NLRP3 inflam-masome), which in response to certain stimuli activates acascade of interactions through caspase 1 that ends inproduction of potent proinflammatory cytokines, mainly IL-1β and IL-18.62

Cryopyrin activation is mediated by PAMPs (pathogen-associated molecular patterns, such as muramyl dipeptides,bacterial or viral RNA), DAMPs (danger-associated molec-ular patterns, such as uric acid crystals, skin irritants orultraviolet B radiation), and maybe alum, used as a vaccineadjuvant.63–65 Different self-activating mutations in theNLRP3 gene cause constitutive activation of inflammasomecomplex and production of proinflammatory IL-1β. Thedifferent clinical manifestations between CAPS reflect theway different mutations affect the activity of the inflamma-some; however, these differences are not really marked andoverlapping cases are commonly seen.65

Familial cold autoinflammatory syndrome (FCAS)

FCAS or familial cold urticaria is the mildest of all CAPS.It is characterized by a constellation of clinical manifestationafter generalized exposure to cold air. Usually it starts duringthe first year of age, even after delivery when the newborn isexposed to a cold maternity room.

Clinical manifestationsSymptoms begin between 2 to 7 hours after generalized

cold exposure and are characterized by an urticarialike skin

Fig. 3 Urticarial lesions in NOMID syndrome.

rash associated with fever, chills, conjuntival injection, andarthralgias. The episode usually resolves in less than 12hours (rarely last 24 hours). Other clinical manifestationsinclude fatigue, headache, and myalgias. In laboratoryanalysis appears a marked leukocytosis 10 hours after coldexposure and starts to diminish 12 to 14 hours latter.Amyloidosis is a very rare complication of FCAS.66,67

Cutaneous manifestationsThe skin eruption consists of erythemato-edematous,

urticarialike papules, and plaques that develop after coldexposure. The contact with a cold object does not induce therash. The lesions may be itchy but more often are burning orstinging and usually display a more symmetrical pattern thatappears in true urticaria.

Histologic examinations reveals a predominant perivas-cular neutrophilic infiltrate without vasculitis, and dermaledema.5,66,68

Muckle-Wells syndrome (MWS)

MWS, also known as urticaria-deafness-amyloidosissyndrome, is a rare condition similar to FCAS but withmore severe manifestations. The episodes usually begin earlyduring childhood, although the age of onset is variable. Thereare multiple triggers, but these cannot always be identified.The most common precipitating factors are exposure to heatand cold.65,69,70

Clinical manifestationsThey consist of intermittent febrile episodes together with

headache, conjunctivitis skin rash, and joint manifestations(arthritis or arthralgia), that are similar to those in FCAS, butlast longer in MWS (12 to 36 hours) and the intervalsbetween episodes are not as regular as in FCAS.69,71

Patients with MWS characteristically present a progressivesensorineural hearing loss that starts in childhood and it mayevolve into complete deafness. This hearing loss is thought tobe secondary to cochlear or leptomeningeal inflammation.

Secondary amyloidosis is a complication of MWS in up toa quarter of patients. Nephropathy may identify in 35% ofMWS caused mostly by renal amyloidosis.69,71

Abnormalities in laboratory analysis express the high levelof inflammation that appears in MWS, with an elevation ofinflammatory markers and leukocytosis during attacks.

Cutaneous manifestationsAn urticarial-like rash, similar to that in FCAS, appears in

MWS. The histologic features are similar to FCAS as well.5

Neonatal onset multisystemic inflammatorydisorder (NOMID)

NOMID, also named as chronic infantile neurologicalcutaneous and articular (CINCA) syndrome, is the most

Fig. 4 The papular eruption of Blau syndrome.

494 P. Dávila-Seijo et al.

severe of the cryopyrinopathies. Most of the cases aresporadic and only a few present an autosomal-dominanttransmission. The same as other CAPS, symptoms appearshortly after birth, usually before 6 months of age. The triadof skin rash, severe arthropathy, and central nervous systemdisorders characterizes NOMID.65,72

Clinical manifestationsRecurrent short episodes of fever are common in NOMID.

Patients show abnormal facial features (Figure 1), generallydeveloped at birth or nearly after, such as flattening of thenasal bridge, macrocephaly, frontal bossing, and protrudingeyes.73 They usually present a constellation of neurologicalmanifestation-like chronic aseptic meningitis, cerebral atro-phy, sensorineural hearing loss, early-morning headachesrelated with increased intracranial pressure, and develop-mental delay. Eye manifestations, including anterior uveitis,papilledema or blindness, are also part of NOMID systemicmanifestations.74

Even though arthropathy is present in variable degrees ofseverity, 50% of patients have severe arthropathy before 12months of age (Figure 2). In mild cases, there is only somepain and joint effusion. In most severe forms, exuberantcartilaginous proliferations with secondary ossificationresembling tumors are seen at growth plates and epiphysesin radiologic studies.75 Other features include lymphadeno-

phaty and hepatosplenomegaly. Secondary amyloidosis mayappear due to chronic inflammation.1,5

Laboratory findings include acute-phase reactants eleva-tion, leukocytosis, thrombocytosis and eosinophilia, andserum hyperglobulinemia.

Cutaneous manifestationsA migratory, nonpruritic, erythematous skin eruption

resembling urticaria appears in most cases before 6 monthsof age (Figure 3); two-thirds of newborns have skin lesions atbirth. The rash persists during the whole life of patients.Histologic features are superficial and deep perivascularinfiltrates composed mainly of lymphocytes, neuthrophils,and some eosinophils. Mast cells are absent and epidermis ispreserved.76 Neutrophilic eccrine hidradenitis has beenreported as well in NOMID.77

Therapy of CAPS

Anakinra, the IL-1 receptor antagonist, given in dailysubcutaneous injections, has shown marked capacity inpreventing attacks and reducing inflammation manifestationsin FCAS and MWS, reducing the risk of developingsecondary amiloydosis also. The role of anakinra inpreventing hearing loss is not clear in MWS, but somepartial recovery has been reported in several cases. Anakinraseems also effective in reducing inflammation in some casesof NOMID, but not all patients respond and apparently itdoes not play an important role in decreasing joint and bonealterations.78

Rilonacept, an IL-1 trap given subcutaneous on weeklybasis, appears as an effective agent in decreasing signs andsymptoms of inflammation in FCAS and MWS withoutsevere adverse effects.78

Treatment with canakinumab, a human anti-IL-1βmonoclonal antibody, showed complete and sustainedresponses in almost all cases of CAPS in a randomizedplacebo-controlled trial. A significant increase in theincidence of suspected infections appeared in the canakinu-mab group.78

Deficiency of the interleukin-1-receptor antagonistsyndrome (DIRA)

DIRA is a rare autosomal recessive autoinflammatorysyndrome due to deficiency of the interleukin-1-receptorantagonist (IL1RN).

EtiologyDIRA share etiopathogenic features with CAPS but

clinical manifestations differ from them. The deficiency ofinterleukin-1-receptor is secondary to homozygous germ linemutations in IL1RN (single point mutations, deletions, andmicrodelections have been reported).79–82 These mutationsproduce a protein, which lacks antagonistic activity of IL-1

495Autoinflammatory syndromes

receptor leading to a continuous activation of inflammatorypathways through IL-1. Heterozygous carriers are usuallyasymptomatic or may have mild manifestations.

Clinical manifestationsCharacteristically, DIRA patients present chronic recur-

rent episodes of multifocal aseptic osteomyelitis andperiostitis at birth or within 2 months postpartum. Recently,a case of a fetus with clinical manifestation of DIRA has beenreported.83 Other skeletal manifestations include osteopenia,periarticular swelling secondary to long-bone epiphysealovergrowth, cervical vertebral fusion, and widening ofclavicle and anterior rib ends. Fever and failure to thriveare present commonly in DIRA. Other clinical manifesta-tions in DIRA are respiratory distress, pulmonary infiltrates,thrombotic episodes, and vasculitis. Laboratory analysesshow an increase in acute-phase reactants, mild anemia, andblood leukocytosis with neutrophilia.79,80,84

Cutaneous manifestationsGeneralized erytematous plaques with overlying pus-

tules, simulating generalized pustular psoriasis, appear atbirth or during the first 2 months of age. This severepustular skin rash, that usually respects palms and soles,may result in diffuse desquamation. Nail changes (mostlypitting but also anonychia) are common in DIRA. Mucouslesions, mostly in the form of a vesicular stomatitis ormouth ulcers, are also described. Pathergy reaction hasbeen reported.79,80,84

Skin lesion biopsies show epidermal parakeratosis withsubcorneal acantholitic or spongiform neutrophilic pustules,dermal neutrophilic infiltrates with concomitant superficialfolliculitis and/or neutrophilic eccrine hidradenitis. Inmuno-fluorescence studies are negative.79,80,84

Therapy

Daily subcutaneous injections with anakinra, the recom-binant analogue of IL1RN, 1 to 5 mg/kg, has led to

Fig. 5 Sarcoid-like granulomas in Blau syndrome.

complete clinical resolution of cutaneous and osteoarticularmanifestations in most patients with DIRA and partialresolution in some of them. This variable response totreatment with anakinra seems to have a genetic relationwith mutations that lead to a more severe or unresponsivedisease. Treatment with NSAIDs, corticosteroids, and otherimmunomodulatory drugs was either noneffective or onlypartially effective.79–82,84

Other pustular autoinflammatory syndromes

Deficiency of interleukin thirty-six-receptor antagonistsyndrome (DITRA)

Recently, mutations in the IL-36 receptor antagonist(IL36RN) were identified as the cause of some familial andsporadic cases of generalized pustular psoriasis (GPP).85,86

The new disorder of IL-36-receptor antagonist associatedGPP has been named DITRA syndrome.86

EtiologyLoss-of-function homozygous mutations in IL36RN gene

were shown to be the cause of familial and sporadic cases ofDITRA. In familial cases the disorder has an autosomalrecessive inheritance. IL36RN is a protein of the IL-1cytokine family, which is abundantly expressed in the skinand that has an important role in inflammatory pathways,such as the NF-κB, blocking the recruitment of interleukin-1receptorlike 2 (IL-1 RL2) receptor through its inhibition ofIL-36 α and IL-36 γ, which has been found in higher levelsin skin lesions in DITRA patients in response to IL-1 β andpolyosinic-polycytidylic acid stimuli.85–87

Clinical manifestationsDITRA is characterized by sudden and recurrent episodes

of skin eruption together with fever, malaise, and astheniawithout involvement of other organs. There is an increasedrisk of death due to sepsis during the flares. The frequency ofepisodes is variable. They usually begin during the childhoodbut some adult onset cases were reported as well. Somereported triggers have been bacterial and viral infections,menstruation, pregnancy or drugs.85,86

Cutaneous manifestationsThe skin lesions in DITRA resemble GPP: a rapid onset of

generalized pustular eruption over erythematous skin.Psoriasis vulgaris lesions and acral pustular lesions withnail destruction are also found in some patients. Interesting-ly, palmoplantar pustulosis seems to not be part of theclinical spectrum of DIRA syndrome. The histologic studiesshow the typical features of pustular psoriasis: spongiformpustules, psoriasiform acanthosis, and parakeratosis in thestratum corneum.86

TherapyAnakinra, the recombinat IL-1 receptor antagonist has

been reported to be effective in some cases of GPP.88

Fig. 6 Panniculitis as a sign of Blau syndrome.

496 P. Dávila-Seijo et al.

Other autoinflammatory syndromes

Pyogenic arthritis, pyoderma gangrenosum andacne syndrome (PAPA)

PAPA, also named familial recurrent arthritis, is a veryuncommon autosomal-dominant disease characterized by thepresence of pyogenic arthritis, pyoderma gangrenosum, andcystic acne.89

EtiologyThe gene found to be responsible for this syndrome is the

proline/serine/threonine phosphatase-interacting protein 1(PSTPIP1; also known as CD2 antigen-binding protein 1[CD2BP1]) localized on chromosome 15 q24-25.1. Itsproduct, PSTPIP1, is a cytoskeletal protein expressedpredominantly in hematopoietic cells that modulates T cellactivation, cytoskeletal organization, and interleukin-1 β(IL-1 β) release. When it is mutated there is a disruption ofPSTPIP1 with protein tyrosine phosphatase-PEST thatincreases its avidity for pyrin that causes overproduction ofIL-1 β.89,90 A recent report showed a PAPA case withoutPSTPIP1 mutation.91

Clinical manifestationsRecurrent episodes of sterile arthritis, spontaneous or

following minor trauma, leading to join destruction thatappear during childhood are the hallmark of PAPA. Theyusually tend to decrease its frequency after puberty. Otherless frequent clinical manifestations are recurrent otitis,pharyngeal papillomatosis, lymphadenopathy, splenomega-ly, thrombocytopenia, hypergammaglobulinemia, hemolyticanemia, and T cell large granular lymphocytosis.92,93

Cutaneous manifestationsUsually skin lesions begin during childhood but they

become worse at puberty. They consist essentially of severecystic acne, pathergy phenomenon and recurrent sterileulcers with peripheral undermined borders, and cribiformscarring similar to those seen in pyoderma gangrenosum.

Patients with milder skin manifestations similar topsoriasis and rosacea have also been reported.92,93

TherapyAntitumor necrosis factor (TNF) drugs, infliximab,

adalimumab, and etanercept, appear to be the most effectivetherapy in PAPA syndrome, but not all patients respond.Anakinra was used in PAPA with variable results: somepatients showed marked improvement whereas others onlyobtained a partial benefit. Corticosteroids seem to beeffective for arthritis, but less beneficial in treating pyodermagangresnosum lesions. Other immunosuppressants arepartially or noneffective, although the combination ofsulfasalazine and leflunomide induced remission in onereported case.93,94

NOD2-associated pediatric granulomatous arthritis(PGA): Blau syndrome/early-onset sarcoidosis

Under the name of PGE there are two diseases with anidentical phenotype: One autosomal-dominant disease, alsoknown as Blau syndrome, and one sporadic condition orearly-onset sarcoidosis. Thanks to genetic analyses, we nowknow that there are common mutations in the NOD2 gene(also known as CARD15) in all patients with Blau syndromeand most of patients with early-onset sarcoidosis confirmingthe same etiology of both conditions and supporting thenotion that they are, in fact, the same disease.95–97 That iswhy the common denomination of NOD2-associated PGAmay be preferable, reserving the denomination of early-onsetsarcoidosis for those patients who have similar phenotypewithout identifiable mutation in the NOD2 gene.98,99

EtiologyThe NOD2 gene is mapped to chromosome 16 q12-21.

Mutations in the NOD2 gene are also related with Crohn´sdisease but they differ from those found in NOD2-associated PGA. Mutations in NOD2 identified in NOD-associated PGA are missense mutations resulting inconstitutive self-activation of NOD2, thus leading toincreased basal NFκB activation. In contrast, NOD2mutations associated with Crohn´s disease produce adecrease in NOD2 function, and, hence, in the NFκBpathway. NOD2 protein, mostly expressed in the cytoplasmof hematopoietic cells and in the epithelium of the smallintestine, has a role in the innate response to microorgan-isms recognizing components of bacterial wall muramyldipeptide that leads to activation of NFκB.100

Clinical manifestationsClassic clinical manifestations are characterized by the

triad of early-onset of polyarticular boggy synovitis,

Fig. 7 CANDLE syndrome: Annular purpuric plaques.

497Autoinflammatory syndromes

granulomatous acute anterior uveitis, and skin rash.101 Thejoint manifestations begin before the age of 10 as painless,cystic lesions on feet and wrists together with mildboutonniere deformities of the fingers. With time, theydevelop camptodactily with cystic swelling of the wrists,ankles, knees, and elbows. These joint anomalies are slowlyprogressive and they do not limit mobility until severaldecades after beginning. In histologic studies of synovialmembrane appears granulomatous inflammation with giantmultinucleated cells.102

Eye involvement, with recurrent episodes of anterioruveitis that may progress to posterior involvement, canlead to cataracts, glaucoma, and even blindness years afterinitial symptoms, which may start early in childhood orduring adulthood.

Other nonclassic manifestations described in NOD2-associated PGA are mild to moderate nonperiodic fever,granulomatous lymphadenopaty, multiple asymptomatichepatic epithelioid granulomas, hepatosplenomegaly, gran-ulomatous infiltration of salivary glands, pneumonitis,granulomatous glomerulonephitis, and intersticial nephritisand cranial neuropathy.102

Cutaneous manifestationsCharacteristic skin lesions are one of the three main

features of classic NOD2-associated PGA. These lesions areusually observed in early childhood and consist inasymptomatic tiny red or tan, sometimes lichenoid papulesthat may be localized or generalized in trunk and extremitiessparring the palms and soles (Figure 4). The skin lesions canbe so inconspicuous that may be missed. Histologicalexaminations show noncaseating granulomas in dermiswith multiple epithelioid and multinucleated giant cellsindistinguishable from sarcoidosis (Figure 5). Electronmicroscopy may show the characteristic “comma-shapedbodies” inside epithelioid cells, but they are not alwayspresent.98,99,101,102

Other cutaneous manifestations described in NOD2-associated PGA have been panniculitis related with febrileepisodes clinically resembling erythema nodosum (Figure 6)

and leukocytoclastic vasculitis with maculopapular andurticarial rash.98

TherapyCutaneous lesions may respond to chronic therapy with

erythromycin. NSAIDs, corticosteroids, methotrexate, andanti-TNF drugs are the usual therapies for extracutaneousmanifestations. Thalidomide has been reported to show goodefficacy in this disorder. There are occasional reports of theresponse with the use of anakinra.103

Majeed syndrome

The hallmark of this disorder is the presence of a chronicrecurrent multifocal osteomyelitis (CRMO) and congenitaldyserythropoietic anemia (CDA) with microcytosis, some-times associated with inflammatory dermatosis.104,105

The disease usually starts during the first year of age butno later than the age of two and presents clinicalexacerbations and remissions.

EtiologyDifferent homozygous mutations in LPIN2 gene have

been found in Majeed patients.106–108 LPIN2 is a protein thatshares the lipin domine with LPIN1 and LPIN3, all these arephosphatidate phosphatase (PAPs). PAPs play an importantrole in glycerolipid biosynthesis and act as transcriptioncoactivators regulating lipid metabolism genes. The muta-tions reported in Majeed syndrome appear to abolish thePAPs function. Also, LPIN2 may be increased in response tooxidative stress and play a role in mitoses. Although, themechanism by which mutations in LPIN2 cause Majeedsyndrome is unclear it seems that IL-1 may be important inpathogenesis due to the good response to therapy with an IL-1receptor antagonist.

Clinical manifestationsOnset of CRMO in Majeed syndrome begins earlier (3

weeks to 2 years) than in the isolated form of CRMO (4 to 15years of age), and also shows shorter remissions, anincreased number of exacerbations and a prolonged coursewith poor tendency to autoresolution.105

Each exacerbation consists of high fever, pain, andswelling, mainly around large joints. As a consequence,growth delay and permanent flexion contractures may ensue.Radiological studies have shown that changes resemblebacterial osteomyelitis: osteolytic lesions with surroundingsclerosis. Biopsy of bone lesions shows nonspecificinflammatory changes.109

CDA usually presents during the first year of life ashypochromic, microcytic anemia and its severity is variable.Bone marrow examination evidences increased erythropoi-esis associated with dyserythropoiesis including binucleatedand trinucleated normoblasts.109

Fig. 8 CANDLE syndrome: Mononuclear infiltrate of the skinwith bizarre nuclei.

498 P. Dávila-Seijo et al.

Individuals with Majeed syndrome have also growthretardation with short stature.105

Cutaneous manifestationsThe inflammatory dermatosis is not a consistent pheno-

typic component of Majeed syndrome. To date, two patientshad Sweet syndrome, another one showed a “cutaneouspustulosis,” and a heterozygous carrier was affectedwith psoriasis.109

TherapyThe main therapy of CRMO is NSAIDs, which provide

moderate improvement. Corticosteroids are also useful incontrolling CRMO and skin manifestations. Recently therewere reported two cases of Majeed syndrome with noresponse to corticosteroids and etanercept that showed acomplete and maintained response to anakinra and canaki-numab (anti-Il-1 β antibody).107

Fig. 9 Lipodystrophy in CANDLE syndrome.

Chronic atypical neutrophilic dermatosiswith lipodystrophy and elevated temperature(CANDLE) syndrome

CANDLE syndrome is a recently described entitycharacterized by recurrent episodes of fever, cutaneouslesions, lipodystrophy, and visceral inflammatory manifes-tations.110 The clinical manifestations begin during the firstyear of age, generally during the first weeks, and show notendency to autoresolution.

EtiologyIn a recent report, genetic analyses were performed on

nine patients with clinical CANDLE syndrome, findinghomozygous and compound heterozygous mutations inPSMB8, encoding the immunoproteasome subunit β5 i inmost of them.111 None of these were observed in healthycontrols. All patients expressed high levels of interferon-γ

(IFNγ)–inducible protein 10 (IP-10). CANDLE syndrome,caused by mutations in PSMB8, is allelic with “JMP”syndrome (joint contractures, muscle atrophy, microcyticanemia, and panniculitis-induced childhood-onset lipody-strophy) and a similar phenotype named the Nakajo-Nishimura syndrome in Japan. The proteasome/immunopro-teasome are key cell structures to cleave and eliminateubiquitinized proteins fated to be removed; in the absence ofimmunoproteasome assembly or decreased catalytic func-tion, polyubiquitinized proteins accumulate in the cytoplasmof macrophages, leading to cellular stress; in turn, cellularstress activates JAK kinase and production of interferons,leading to more cellular stress and accumulation of stressproteins that cannot be adequately removed, thus leading to acircle of increasing cellular stress.111

Clinical manifestationsDaily or recurrent episodes of fever (higher than 38 °C)

are characteristic in CANDLE syndrome. Low weight andheight are always present. Hepatomegaly, splenomegaly, andarthralgia without arthritis are common features. A constel-lation of inflammatory manifestations were described inCANDLE patients, such as ear and nose chondritis,conjunctivitis and nodular episcleritis, epididimitis, nephri-tis, otitis, parotitis, aseptic meningitis, or lymphadenopathy.Laboratory analyses evidence chronic anemia, elevation ofacute-phase reactants, and mild raise of liver enzymes.110

Cutaneous manifestationsRecurrent annular erythematous, edematous plaques with

raised borders, are one of the hallmarks of CANDLE andthey have been seen in all reported patients (Figure 7). These

Fig. 10 Violaceous periorbital erythema in CANDLE syndrome.

499Autoinflammatory syndromes

lesions appear predominantly on the trunk but also on theface and limbs, especially over the interphalangeal joints.Usually, they spontaneously resolved leaving hyperpig-mented or ecchymosislike residual lesions. New plaquesare continuously appearing resulting in a chronic skineruption. Histologic examination of these lesions showsdense dermal perivascular and intersticial infiltratessometimes with subcutaneous involvement, composed ofmononuclear myeloid cells with atypical features resem-bling leukemia cutis, with increased number of mitoticfigures (Figure 8). A variable number of neutrophils andeosinophils may be present mixed together with the atypicalmyeloid cells.110

Progressive lipodysthrophy in the face, upper extremities,and trunk is a consistent clinical manifestation as well(Figure 9). Persistent purplish eyelid swelling and perioralswelling are quite common (Figure 10).

TherapyNSAIDs where used with partial control of fever.

Corticosteroids are also only partially effective in controllingthe symptoms. Other antiinflammatory drugs such colchicine,dapsone, cyclosporin, immunoglobulin infusions, and meth-otrexate were used with little or no improvement. Anti-TNFαdrugs, such as etanercept and infliximab, were attempted withexacerbation of skin lesions and no improvement, respectively.Anakinra was also tried unsuccessfully.110

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